Preliminary research indicates that it may help with drug addiction;[3] however, there is a lack of data in humans.[4] Its use has been associated with serious side effects and death. Between the years 1990 and 2008 a total of 19 fatalities temporally associated with the ingestion of ibogaine were reported, from which six subjects died of acute heart failure or cardiopulmonary arrest. The total number of subjects who have used it without major side effects during this period remains unknown.[3] It is used as an alternative medicine treatment for drug addiction in some countries. Its prohibition in other countries has slowed scientific research.[5] Ibogaine is also used to facilitate psychological introspection and spiritual exploration. Derivatives of ibogaine that lack the substance's psychedelic properties are under development.[6]

The psychoactivity of the root barks of the iboga tree (Tabernanthe iboga), from which ibogaine is extracted, was first discovered by the Pygmy tribe of Central Africa who passed the knowledge to the Bwiti tribe of Gabon. French explorers in turn learned of it from the Bwiti tribe and brought iboga back to Europe in 1899-1900 where it was subsequently marketed in France as Lambarene. Ibogaine-containing preparations are used for medicinal and ritual purposes within African spiritual traditions of the Bwiti, who claim to have learned it from the Pygmy peoples. Although it was first commonly advertised as having anti-addictive properties in 1962 by Howard Lotsof, its Western use predates that by at least a century. In France it was marketed as Lambarène and used as a stimulant. Also, the U.S. Central Intelligence Agency (CIA) studied the effects of ibogaine in the 1950s.[7]

Psychoactive effects

Ibogaine is derived from the root of the Tabernanthe iboga, a plant known to exhibit psychedelic effects in its users.[13] The experience of ibogaine occurs in two phases, the visionary phase and the introspection phase. The visionary phase has been described as oneirogenic, referring to the dreamlike nature of its psychedelic effects, and lasts for 4 to 6 hours. The second phase, the introspection phase, is responsible for the psychotherapeutic effects. It can allow people to conquer their fears and negative emotions. Ibogaine catalyzes an altered state of consciousness reminiscent of dreaming while fully conscious and aware so that memories, life experiences, and issues of trauma can be processed.[14]

Uses

Medical

Ibogaine is not currently approved for any medical uses.[3] Clinical studies of ibogaine to treat drug addiction began in the early 1990s, but concerns about cardiotoxicity led to termination of those studies.[4] There is currently insufficient data to determine whether it is useful in treating addiction. Nonetheless, some alternative medicine clinics administer ibogaine for this purpose, in what has been called a "vast, uncontrolled experiment."[15] Clinical trials of Ibogaine for the treatment of alcoholism are currently underway in Brazil.[16]

Religious

In Bwiti religious ceremonies, the root bark is pulverized and swallowed in large amounts to produce intense psychoactive effects.[17]

Adverse effects

Immediate

One of the first noticeable effects of large-dose ibogaine ingestion is ataxia, a difficulty in coordinating muscle motion which makes standing and walking difficult without assistance. Xerostomia (dry mouth), nausea, and vomiting may follow. These symptoms may be long in duration, ranging from 4 to 24 hours in some cases. Ibogaine is sometimes administered per rectum to avoid nausea and vomiting.

Cardiovascular

Neurotoxicity

Work in the laboratory of Mark Molliver at Johns Hopkins indicated degeneration of cerebellar Purkinje cells observed in rats given substantially larger dosages of ibogaine than those used to study drug self-administration and withdrawal.[19] However, subsequent research found no evidence of neurotoxicity in the primate[20] or mouse[21] at dosages that produced cerebellar degeneration in the rat, and it has been suggested that cerebellar degeneration might be a phenomenon limited to a single species.[22] The FDA was aware of Molliver’s work at the time it approved a Phase 1 study in which humans received ibogaine in 1993.[23] Neuropathological examination revealed no evidence of degenerative changes in a woman who had received four separate doses of ibogaine ranging between 10 and 30 mg⁄ kg over a 15-month interval prior to her death due to a mesenteric artery thrombosis with small bowel infarction 25 days after her last ingestion of ibogaine.[20] A published series of fatalities temporally associated with the ingestion of ibogaine found no evidence suggesting a characteristic syndrome of neurotoxicity.[24]

Interactions

Adverse interactions may occur between ibogaine and psychiatric medications. Some studies also suggest the possibility of adverse interaction with heart conditions.[18][3][24]

Because ibogaine is one of the many drugs that are partly metabolized by the cytochrome P450 complex, caution must be exercised to avoid foods or drugs that are similarly metabolized by CP450, in particular foods containing bergamottin or bergamot oil, such as grapefruit juice.[25]

Noribogaine is most potent as a serotonin reuptake inhibitor. It acts as a moderate κ-opioid receptor agonist[29] and weak µ-opioid receptor agonist[30] or weak partial agonist.[31] It is possible that the action of ibogaine at the kappa opioid receptor may indeed contribute significantly to the psychoactive effects attributed to ibogaine ingestion; Salvia divinorum, another plant recognized for its strong hallucinogenic properties, contains the chemical salvinorin A which is a highly selective kappa opioid agonist. Noribogaine is more potent than ibogaine in rat drug discrimination assays when tested for the subjective effects of ibogaine.[32]

Pharmacokinetics

Ibogaine is metabolized in the human body by cytochrome P450 2D6 into noribogaine (more correctly, O-desmethylibogaine or 12-hydroxyibogamine). Both ibogaine and noribogaine have a plasma half-life of around two hours in the rat,[33] although the half-life of noribogaine is slightly longer than that of the parent compound. It is proposed that ibogaine is deposited in fat and metabolized into noribogaine as it is released.[34] After ibogaine ingestion in humans, noribogaine shows higher plasma levels than ibogaine and is detected for a longer period of time than ibogaine.[35]

Chemistry

The general structure of tryptamines.

Ibogaine is a tryptamine. It has two separate chiral centers, meaning that there are four different stereoisomers of ibogaine. These four isomers are difficult to resolve.[36]

Synthesis

One recent total synthesis[37] of ibogaine and related drugs starts with 2-iodo-4-methoxyaniline which is reacted with triethyl((4-(triethylsilyl)but-3-yn-1-yl)oxy)silane using palladium acetate in DMF to form 2-(triethylsilyl)-3-(2-((triethylsilyl)oxy)ethyl)-1H-indole. This is converted using N-iodosuccinamide and then fluoride to form 2-(2-iodo-1H-indol-3-yl)ethanol. This is treated with iodine, triphenyl phosphine and imidazole to form 2-iodo-3-(2-iodoethyl)-1H-indole. Then using 7-ethyl-2-azabicyclo[2.2.2]oct-5-ene and cesiumcarbonate in acetonitrile the ibogaine precursor 7-ethyl-2-(2-(2-iodo-1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene is obtained. Using palladium acetate in DMF the ibogaine is obtained. If the exo ethyl group on the 2-azabicyclo[2.2.2]octane system in ibogaine is replaced with an endo ethyl then epiibogaine is formed.

Crystalline ibogaine hydrochloride is typically produced by semi-synthesis from voacangine in commercial laboratories.[17][38]

Derivatives

A synthetic derivative of ibogaine, 18-methoxycoronaridine (18-MC), is a selective α3β4 antagonist that was developed collaboratively by the neurologist Stanley D. Glick (Albany) and the chemist Martin E. Kuehne (Vermont).[39] This discovery was stimulated by earlier studies on other naturally occurring analogues of ibogaine such as coronaridine and voacangine that showed these compounds also have anti-addictive properties.[40][41]

Natural occurrence

Ibogaine occurs naturally in iboga root bark. Ibogaine is also available in a total alkaloid extract of the Tabernanthe iboga plant, which also contains all the other iboga alkaloids and thus has only about half the potency by weight as standardized ibogaine hydrochloride.[17]

History

The use of iboga in African spiritual ceremonies was first reported by French and Belgian explorers in the 19th century. The first botanical description of the Tabernanthe iboga plant was made in 1889. Ibogaine was first isolated from T. iboga in 1901 by Dybowski and Landrin[42] and independently by Haller and Heckel in the same year using T. iboga samples from Gabon. Complete synthesis of ibogaine was accomplished by G. Büchi in 1966.[43] Since then, several other synthesis methods have been developed.[44]

From the 1930s to 1960s, ibogaine was sold in France in the form of Lambarène, an extract of the Tabernanthe manii plant, and promoted as a mental and physical stimulant. The drug enjoyed some popularity among post World War II athletes. Lambarène was withdrawn from the market in 1966 when the sale of ibogaine-containing products became illegal in France.[45]

Anecdotal reports concerning ibogaine's effects appeared in the early 1960s.[47] Its anti-addictive properties were discovered accidentally by Howard Lotsof in 1962, at the age of 19, when he and five friends—all heroin addicts—noted subjective reduction of their craving and withdrawal symptoms while taking it.[48] Further anecdotal observation convinced Lotsof of its potential usefulness in treating substance addictions. He contracted with a Belgian company to produce ibogaine in tablet form for clinical trials in the Netherlands, and was awarded a United States patent for the product in 1985. The first objective, placebo-controlled evidence of Ibogaine's ability to attenuate opioid withdrawal in rats was published by Dzoljic et al. in 1988.[49] Diminution of morphine self-administration was reported in preclinical studies by Glick et al. in 1991.[50] Cappendijk et al. demonstrated reduction in cocaine self-administration in rats in 1993,[51] and Rezvani reported reduced alcohol dependence in three strains of "alcohol preferring" rats in 1995.[52]

As the use of ibogaine spread, its administration varied widely; some groups administered it systematically using well developed methods and medical personnel, while others employed haphazard and possibly dangerous methodology. Lotsof and his colleagues, committed to the traditional administration of ibogaine, developed treatment regimens themselves. In 1992, Eric Taub brought ibogaine to an offshore location close to the United States, where he began providing treatments and popularizing its use.[53] In Costa Rica Lex Kogan, another leading proponent, joined Taub in systematizing its administration. The two men established medically monitored treatment clinics in several countries.[54]

In 1981 an unnamed European manufacturer produced 44 kg of iboga extract. The entire stock was purchased by Carl Waltenburg, who distributed it under the name "Indra extract" and used it in 1982 to treat heroin addicts in Christiania, Denmark, a squatter village where heroin addiction was widespread.[55] Indra extract was available for sale over the Internet until 2006, when the Indra web presence disappeared. Various products are currently sold in a number of countries as "Indra extract", but it is unclear if any of them are derived from Waltenburg's original stock. Ibogaine and related indole compounds are susceptible to oxidation over time.[56][57]

The National Institute on Drug Abuse (NIDA) began funding clinical studies of ibogaine in the United States in the early 1990s, but terminated the project in 1995.[58] Data demonstrating ibogaine's efficacy in attenuating opioid withdrawal in drug-dependent human subjects was published by Alper et al. in 1999.[59] A cohort of 33 patients were treated with 6 to 29 mg/kg of ibogaine; 25 displayed resolution of the signs of opioid withdrawal from 24 hours to 72 hours post-treatment, but one 24-year-old female, who received the highest dosage, died. Mash et al., (2000) using lower oral doses (10–12 mg/kg) in 27 patients, demonstrated significantly lower objective opiate withdrawal scores in heroin addicts 36 hours after treatment, with self-reports of decreased cocaine and opiate craving and alleviated depression symptoms. Many of these effects appeared sustainable over a one-month post-discharge follow-up.[60]

Society and culture

Legal status

The Global Ibogaine Therapy Alliance publish a map of ibogaine legal status in various countries around the world.[61]

Brazil

On 14 January 2016, Ibogaine was legalized for prescription use in São Paulo, Brazil, with this legalization to extend to the rest of the country in a few months.[62]

Canada

Ibogaine was unregulated in Canada in 2009.[63][64] Then Health Canada added ibogaine to the Prescription Drug List (PDL) in 2017.[65]

Germany

Ibogaine is unregulated in Germany, but for medical use it can be regulated by the pharmacy rules (AMG).

New Zealand

Ibogaine was gazetted in New Zealand in 2009 as a non-approved prescription medicine.[66]

Norway

Ibogaine is illegal in Norway (as are all tryptamine derivatives).[67]

Sweden

United Kingdom

As of January 2017 in the United Kingdom, ibogaine was an unlicensed medical product.[69]

United States

Ibogaine is classified as a Schedule I-controlled substance in the United States,[70] and is not approved there for addiction treatment (or any other therapeutic use) because of its hallucinogenic, neurotoxic, and cardiovascular side effects, as well as the scarcity of safety and efficacy data in human subjects.[71]

Treatment clinics

Ibogaine treatment clinics have emerged in Mexico, Canada, the Netherlands, South Africa, and New Zealand, all operating in what has been described as a "legal gray area".[72][73]Costa Rica also has treatment centers, most notably one run by Lex Kogan, a leading proponent of ibogaine.[74] Covert, illegal neighborhood clinics are known to exist in the United States, despite active DEA surveillance.[75] While clinical guidelines for ibogaine-assisted detoxification were released by the Global Ibogaine Therapy Alliance in 2015,[76][77] addiction specialists warn that the treatment of drug dependence with ibogaine in non-medical settings, without expert supervision and unaccompanied by appropriate psychosocial care, can be dangerous — and, in approximately one case in 300, potentially fatal.[73]

Media

Documentary films

Detox or Die (2004)

Directed by David Graham Scott.[78] David Graham Scott begins videotaping his heroin-addicted friends. Before long, he himself is addicted to the drug. He eventually turns the camera to himself and his family. After 12 years of debilitating, painful dependence on methadone, Scott turns to ibogaine. Filmed in Scotland and England, and broadcast on BBC One as the third instalment in the documentary series One Life.[79]

Ibogaine: Rite of Passage (2004)

Directed by Ben Deloenen.[80] Cy a 34-year-old heroin addict undergoes ibogaine treatment with Dr Martin Polanco at the Ibogaine Association, a clinic in Rosarito Mexico. Deloenen interviews people formerly addicted to heroin, cocaine, and methamphetamine, who share their perspectives about ibogaine treatment. In Gabon, a Babongo woman receives iboga root for her depressive malaise. Deloenen visually contrasts this Western, clinical use of ibogaine with the Bwiti use of iboga root, but emphasizes the Western context.

Facing the Habit (2007)

Directed by Magnolia Martin.[81] Martin's subject is a former millionaire and stockbroker who travels to Mexico for ibogaine treatment for heroin addiction.

Tripping in Amsterdam (2008)

In this short film directed by Jan Bednarz, Simon "Swany" Wan visits Sara Glatt's iboga treatment center in Amsterdam.[82]Current TV broadcast the documentary in 2008, as part of their "Quarter-life Crisis" programming roster.

In one of five segments from this episode of Drugs, Inc. on National Geographic Channel, a former heroin user treats addicts with ibogaine in Canada. He himself used ibogaine to stop his abuse of narcotics.:[84]

"Addiction" (2013)

This episode of the HBO documentary series Vice[85] devotes a segment to the use of ibogaine to interrupt heroin addiction.

"The Ibogaine Safari" (2014)

A documentary by film maker Pierre le Roux, investigating the claims of painless withdrawal from Opiates such as Njope/Heroin in South Africa by taking several addicts on an adventure 'safari' while taking Ibogaine. The documentary won the award of excellence for 'Best documentary short' at the 2014 Canada International film festival.[86]

Radio

"Sink or Swim. Act Two. I'm Not A Doctor But I Play One At The Holiday Inn.". This American Life. Episode 321. 1 December 2006. — A former heroin addict realizes that he wants to help other addicts kick their habits. The problem is, he wants to do this using a hallucinogenic drug - ibogaine - that is completely illegal, and which requires medical expertise he doesn't have.[99]

Research

Addiction treatment

The most-studied therapeutic effect of ibogaine is the reduction or elimination of addiction to opioids. An integral effect is the alleviation of symptoms of opioid withdrawal. Research also suggests that ibogaine may be useful in treating dependence on other substances such as alcohol, methamphetamine, and nicotine and may affect compulsive behavioral patterns not involving substance abuse or chemical dependence. Researchers note that there remains a "need for systematic investigation in a conventional clinical research setting."[47]

Many users of ibogaine report experiencing visual phenomena during a waking dream state, such as instructive replays of life events that led to their addiction, while others report therapeutic shamanic visions that help them conquer the fears and negative emotions that might drive their addiction. It is proposed that intensive counseling, therapy and aftercare during the interruption period following treatment is of significant value. Some individuals require a second or third treatment session with ibogaine over the course of the next 12 to 18 months. A minority of individuals relapse completely into opiate addiction within days or weeks. A comprehensive article (Lotsof 1995) on the subject of ibogaine therapy detailing the procedure, effects and aftereffects is found in "Ibogaine in the Treatment of Chemical Dependence Disorders: Clinical Perspectives".[100] Ibogaine has also been reported in multiple small-study cohorts to reduce cravings for methamphetamine.[101]

There is also evidence that this type of treatment works with LSD, which has been shown to have a therapeutic effect on alcoholism. Both ibogaine and LSD appear to be effective for encouraging introspection and giving the user occasion to reflect on the sources of their addiction, while also producing an intense, transformative experience that can put established patterns of behaviour into perspective;[102] ibogaine has the added benefit of preventing withdrawal effects.[47]

Chronic pain management

In 1957, Jurg Schneider, a pharmacologist at CIBA (now a division of Novartis), found that ibogaine potentiated morphineanalgesia.[103] No additional data was ever published by CIBA researchers on ibogaine–opioid interactions. Almost 50 years later, Patrick Kroupa and Hattie Wells released the first treatment protocol for concomitant administration of ibogaine with opioids in human subjects, indicating that ibogaine reduced tolerance to opioid drugs. Their paper in the Multidisciplinary Association for Psychedelic Studies Journal demonstrated that administration of low "maintenance" doses of ibogaine HCl with opioids decreases tolerance, but noted that ibogaine's potentiating action could make this a risky procedure.[104]